We generated mice with Gs-alpha deficiency in skeletal muscle (MGsKO mice) by repeated matings of muscle heavy chain promoter -cre recombinase transgenic mice with floxed Gs-alpha mice which have loxP recombination sites surrounding Gs-alpha exon 1. MGsKO mice have normal survival and no obvious physical phenotype. MGsKO mice had normal growth and body weight and composition and no changes in food intake and energy expenditure. These results show that loss of Gs-alpha in muscle does not appear to affect whole body energy metabolism on a regular calorie diet. Studies on high fat diet also show no evidence of differences in metabolism. Studies in glucose metabolism (baseline serum chemistries, glucose and insulin tolerance tests, hyperinsulinemic euglycemic clamp studies, and glucose uptake in isolated muscles) show that MGsKO mice are glucose intolerant despite the fact that the mice have normal insulin secretion and hypoglycemic response to administered insulin. In fact studies in isolated muscles show basal glucose uptake to be increased and with no change in glucose uptake in the presence of maximal insulin stimulation, although the increase from baseline with insulin was lower in muscles from MGsKO mice. In addition, muscle glucose uptake in response to the AMP analog AICAR was unaffected, indicating that AMP kinase and its downstream pathways remain intact. Skeletal muscles in MGsKO show significant atrophy with reduced fiber cross-sectional area. In addition, there is a switch in from type 1 (white, fast-twitch) to type 2 (red, slow-twitch) fibers based upon myosin heavy chain subtypes and kinetic properties even though the muscles have reduced mitochondrial content and oxidative capacity and reduced expression of PGC-1alpha, a known transcriptional inducer of mitochondrial oxifation and switch to type 1 fibers. Therefore in MGsKO mice there is a dissociation between the fiber type switch and the expected changes in metabolic properties. These mice have also proven useful to examine the role of troponin processing in cardiac muscle as a compensatory mechanism to reduced beta-adrenergic signaling. More recent studies have suggested that this switch to type 2 muscle is progressive and may be a compensatory mechanism for reduced muscle mass, and may mimic the situation seen in aging and muscle wasting disorders. Studies are ongoing examining the role of Gs signaling in muscle in adaptive thermogenesis. More recent models have confirmed the lack of effect of Gs-alpha signaling in skeletal muscle on energy balance. These models are being studied to examine the role of beta2-adrenergic signaling in muscle on glucose metabolism. Studies are also underway to examine the role of knocking out Gs in both muscle and adipose tissue to see if activation of energy expenditure in muscle is compensating for loss of thermogenesis in adipose tissue resulting from Gs-alpha deficiency.